1/*1 or *1/*2, non-Japanese patient,corresponding to 20% to 30% of baseline. Low lymphocyte counts are maintained with chronic daily dosing [see
Warnings and Precautions (5.1)].
Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. After stoppingMAYZENT treatment, residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after thelast dose [see Warnings and Precautions (5.1)].
Heart Rate and Rhythm
MAYZENT causes a transient reduction in heart rate and atrioventricular conduction upon treatment initiation [seeWarnings and Precautions (5.3)]. The maximum decline in heart rate is seen in the first 6 hours post dose. Autonomicresponses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by siponimodtreatment.
A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of MAYZENT, whichplateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detectedat a higher incidence under MAYZENT treatment, compared to placebo.
No second-degree AV blocks of Mobitz type II or higher degree were observed. Most AV blocks and sinus pausesoccurred above the recommended dose of 2 mg, with notably higher incidence under non-titrated conditions compared todose titration conditions [see Dosage and Administration (2.2, 2.3)].
The decrease in heart rate induced by MAYZENT can be reversed by atropine or isoprenaline.
Beta-Blockers
The negative chronotropic effect of coadministration of siponimod and propranolol was eva luated in a dedicatedpharmacodynamics (PD)/safety study. The addition of propranolol on top of siponimod at steady-state had lesspronounced negative chronotropic effects (less than additive effect) than the addition of siponimod to propranolol atsteady state (additive HR effect) [see Drug Interactions (7.3)].
Cardiac Electrophysiology
In a thorough QT study with doses of 2 mg (recommended dose) and 10 mg (five times the recommended dose)siponimod at steady-state, siponimod treatment resulted in a prolongation of QTc , with the maximum mean (upper boundof the two-sided 90% CI) of 7.8 (9.93) ms at 2 mg dose and 7.2 (9.72) ms at 10 mg dose. There was an absence of doseandexposure-response relationship for QTc effects with the 5-fold dose and exposures achieved by the supratherapeuticdose. No subject had absolute QTcF greater than 480 ms or ΔQTcF greater than 60 ms for siponimod treatment.
Pulmonary Function
Dose-dependent reductions in absolute forced expiratory volume over 1 second were observed in MAYZENT-treatedpatients and were greater than in patients taking placebo [see Warnings and Precautions (5.4)].
12.3 Pharmacokinetics
Siponimod concentration increases in an apparent dose-proportional manner after multiple once-daily doses of siponimod0.3 mg to 20 mg. Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing, andsteady-state levels are approximately 2-3-fold greater than the initial dose. An up-titration regimen is used to reach theclinical therapeutic dose of siponimod of 2 mg after 6 days, and 4 additional days of dosing are required to reach the
steady-state-plasma concentrations.
Absorption
The time (Tmax) to reach maximum plasma concentrations (Cmax) after oral administration of immediate release oraldosage forms of siponimod wa |
